Mechanistic Model‐Informed Proarrhythmic Risk Assessment of Drugs: Review of the “CiPA” Initiative and Design of a Prospective Clinical Validation Study
Citations Over TimeTop 10% of 2017 papers
Abstract
The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic-based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell-derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J-Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.
Related Papers
- → Acquired QT interval prolongation and HERG: implications for drug discovery and development(2004)145 cited
- → Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea‐pig model(2008)75 cited
- → Evolving regulatory paradigm for proarrhythmic risk assessment for new drugs(2016)26 cited
- → In Vivo Effects of the IKr Agonist NS3623 on Cardiac Electrophysiology of the Guinea Pig(2008)32 cited
- → Evaluation of the effects on the QT-interval of 4 artemisinin-based combination therapies with a correction-free and heart rate-free method(2019)25 cited